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Linaclotide (LINZESS) was approved in August 2012 by the Food and Drug Administration (FDA) as a treatment for both irritable bowel syndrome (IBS) with constipation and chronic constipation of unknown cause.[1] It is the first in a new class of drugs that works by targeting proteins in the intestines known as guanylate cyclase-C (GC-C) receptors. In the intestines, stimulating GC-C receptors increases intestinal fluids, causing a laxative effect.[2]
Public Citizen’s Health Research...
Linaclotide (LINZESS) was approved in August 2012 by the Food and Drug Administration (FDA) as a treatment for both irritable bowel syndrome (IBS) with constipation and chronic constipation of unknown cause.[1] It is the first in a new class of drugs that works by targeting proteins in the intestines known as guanylate cyclase-C (GC-C) receptors. In the intestines, stimulating GC-C receptors increases intestinal fluids, causing a laxative effect.[2]
Public Citizen’s Health Research Group has designated linaclotide as Do Not Use because there is currently no evidence that it is safer or more effective than older treatment options for IBS and constipation, such as fiber supplements and saline laxatives. Further, linaclotide is associated with a number of serious risks, including severe and persistent diarrhea and ischemic colitis.[3] Linaclotide’s long-term safety and effectiveness are not known.
FDA approval for linaclotide was based on evidence from four clinical trials — lasting only three to six months — that demonstrated more frequent symptomatic constipation relief in linaclotide-treated patients than in patients taking placebos.[4] For example, more IBS patients treated with linaclotide reported increased bowel movements than those taking placebos (19.5 percent vs. 6.3 percent).[5] Linaclotide’s effectiveness, however, has not been compared to that of other laxatives.
Ischemic colitis
Linaclotide can increase the risk of ischemic colitis, a potentially fatal inflammatory condition that develops when there is insufficient blood flow to the colon, often due to intestinal obstruction. Ischemic colitis can lead to rectal bleeding or bloody stools, as well as inflammation and perforation of the colon. In severe cases, the condition may necessitate surgery.
An FDA medical reviewer unsuccessfully advocated for inclusion of symptoms of ischemic colitis in the drug’s Medication Guide, which is given to patients with their prescription.[6] But the Medication Guide contains no such warning.[7]
The Medication Guide does warn against the risk for intestinal blockage and instructs patients who “develop unusual or severe stomach-area (abdomen) pain, especially [with] bright red, bloody stools or black stools that look like tar” to immediately seek emergency care.
Other gastrointestinal risks
Linaclotide’s product label warns about a possibly increased risk for numerous other gastrointestinal side effects, including diarrhea, abdominal pain and swelling, fecal (stool) incontinence, and stomach flu. Diarrhea, the most frequent adverse effect, was reported by 20 percent of linaclotide-treated patients with IBS, compared to only 3 percent of those taking placebos.[8] More than two-thirds of patients who continued treatment despite diarrhea reported the diarrhea lasting more than one week.[9]
The label for linaclotide also fails to disclose evidence of additional adverse gastrointestinal effects associated with the drug; these include diverticulitis — inflammation or infection of small pouches (diverticula) lining the intestines — as well as perforation and bleeding of the diverticula.[10] Several patients enrolled in the clinical trials discontinued treatment due to intestinal obstruction.[11] Peritonitis (a potentially fatal infection of the abdominal cavity) occurred in one patient taking linaclotide.[12] No such adverse events occurred in patients taking placebos.
Dehydration, fainting and falling
Severe diarrhea can cause body fluid depletion and lead to additional, potentially serious adverse effects associated with dehydration, including orthostatic hypotension (a sudden drop in blood pressure upon standing) and dizziness. During clinical testing, these adverse effects were more frequently reported in linaclotide-treated patients than in those taking placebos.[13]
Despite several cases of syncope (fainting), falls, orthostatic hypotension and dizziness in linaclotide-treated patients during clinical trials,[14] the drug’s product label fails to mention these risks.
Immune reactions
Linaclotide, similar to many therapeutic proteins, can induce an immune response called “immunogenicity” in which the body reacts against the drug, rendering it less effective. Linaclotide mimics naturally occurring proteins called guanylins that are distributed throughout the body and are essential to the functioning of the heart, brain and lungs.[15] Thus, this immune response could hypothetically also render these natural hormones ineffective and, in turn, cause potentially serious adverse effects.[16] Despite these safety concerns, the FDA did not require the manufacturer to conduct immunogenicity testing before approval.[17] The manufacturer convinced the FDA that linaclotide is only minimally absorbed from the intestines and, therefore, is unlikely to cause an immune reaction that could block naturally occurring guanylins in other parts of the body.[18]
In approving linaclotide, the FDA overlooked evidence from pre-approval clinical trials indicating that linaclotide is associated with adverse events suggesting an immune response. These adverse effects include serious allergic reactions, including anaphylaxis (a severe, life-threatening allergic reaction) and urticaria (hives).[19] The FDA required the manufacturer to conduct postmarketing studies of the immunogenicity of linaclotide.[20]
Patient deaths
Six linaclotide-treated subjects died during the clinical trials, but these deaths were deemed due to other causes and unrelated to linaclotide by the manufacturer.[21] Based on the information disclosed by the FDA, it is difficult to verify to what extent linaclotide played a part, if any, in these deaths.
What You Can Do
Due to serious safety concerns and no evidence demonstrating that linaclotide is more effective than existing treatment options for IBS and constipation, we recommend that you not use linaclotide. You should avoid starting linaclotide if you are not taking it currently. If you are already taking it, you should increase fluid intake and consult your doctor about switching to dietary fiber, psyllium or methylcellulose.
References
[1] Ironwood and Allergan Pharmaceuticals. Label: linaclotide (LINZESS). August 2016. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=09beda19-56d6-4a56-afdc-9a77b70b2ef3. Accessed November 15, 2016.
[2] Linaclotide (LINZESS) for constipation. Med Lett Drugs Ther. 2012;54(1403):91-92
[3] Linaclotide. A bacterial enterotoxin derivative with a laxative action, nothing more. Prescrire Int. 2014;23(155):285-288.
[4] Linaclotide (LINZESS) for constipation. Med Lett Drugs Ther. 2012;54(1403):91-92.
[5] Ironwood and Allergan Pharmaceuticals. Label: linaclotide capsule (LINZESS). August 2016. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=09beda19-56d6-4a56-afdc-9a77b70b2ef3. Accessed November 15, 2016.
[6] Griebel D. Division director summary review for LINZESS (linaclotide) NDA 202811. August 29, 2012. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202811Orig1s000SumR.pdf. November 15, 2016. PDF page 44.
[7] Ironwood and Allergan Pharmaceuticals. Label: linaclotide capsule(LINZESS). August 2016. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=09beda19-56d6-4a56-afdc-9a77b70b2ef3. Accessed November 15, 2016.
[8] He R. Cross disciplinary team leader review for LINZESS (linaclotide) NDA 202811. August 8, 2012. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202811Orig1s000CrossR.pdf. PDF page 30.
[9] Ibid. PDF page 31.
[10] Griebel D. Division director summary review for LINZESS (linaclotide) NDA 202811. August 29, 2012. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202811Orig1s000SumR.pdf. Accessed November 15, 2016. PDF page 43.
[11] Dimick-Santos L. Clinical review for LINZESS (linaclotide) NDA 202811. July 17, 2012. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202811Orig1s000MedR.pdf. Accessed November 15, 2016. PDF page 416.
[12] Ibid. PDF page 405.
[13] Wynn E. Clinical review for LINZESS (linaclotide) NDA 202811. August 1, 2012. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202811Orig1s000MedR.pdf. Accessed November 15, 2016. PDF page 247.
[14] Dimick-Santos L. Clinical review for LINZESS (linaclotide) NDA 202811. July 17, 2012. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202811Orig1s000MedR.pdf. Accessed November 15, 2016. PDF pages 404, 430 and 437.
[15] Sindic A. Current understanding of guanylin peptides actions. ISRN Nephrol. 2013: 813648.
[16] Griebel D. Division director summary review for LINZESS (linaclotide) NDA 202811. August 29, 2012. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202811Orig1s000SumR.pdf. Accessed November 15, 2016. PDF page 48.
[17] Dimick-Santos L. Clinical review for LINZESS (linaclotide) NDA 202811. July 17, 2012. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202811Orig1s000MedR.pdf. Accessed November 15, 2016. PDF page 453.
[18] Ibid. PDF pages 453-454.
[19] Ibid. PDF pages 454-457.
[20] Kusiak V. Food and Drug Administration approval letter for LINZESS (linaclotide) NDA 202811. August 30, 2012. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202811Orig1s000Approv.pdf. Accessed November 15, 2016.
[21] Dimick-Santos L. Clinical review for LINZESS (linaclotide) NDA 202811. July 17, 2012. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202811Orig1s000MedR.pdf. Accessed November 15, 2016. PDF page 397.
